Abstract
Coumarin derivatives are effective in the prevention and treatment of thromboembolic diseases. Examples of indications are atrial fibrillation and venous thromboembolism. Although coumarins are on the market for decades, it is still challenging to find the optimal dosage for each patient since coumarins have a small therapeutic index. In trying
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to achieve the optimal anticoagulant effect, the patient constantly balances between a too low anticoagulant effect -which increases the risk of thromboembolic events- and a too high anticoagulant effect -which increases the risk of hemorrhages. In addition, there is a wide inter- and intra-patient variability in coumarin dose requirements. A dosage that provides optimal anticoagulation status in the first patient might cause hemorrhages in a second patient and thromboembolic events in a third. In this thesis, we describe studies that aimed to develop pretreatment personalized dosing strategies for coumarins. A general introduction on the history of coumarins and the pharmacogenetics of oral anticoagulant therapy with coumarins is provided in Chapter 1 and Part I, Chapter 2. In Part II, we discuss the development and usage of the nongenotype- and genotype-guided dose algorithms for phenprocoumon and acenocoumarol. The development and validation of the dose algorithms for phenprocoumon and acenocoumarol is described in Chapter 3. We include information on age, height, weight, sex, and amiodarone use in the nongenotype-guided algorithm. The genotype-guided algorithm includes next to these information on the VKORC1 genotype and CYP2C9 genotype. The genotype-guided dose algorithm explains 55.9% and 52.6% of the variance of the maintenance dose for phenprocoumon and acenocoumarol, respectively while for the nongenotype-guided dose algorithm these percentages were 17.3% and 23.7%, respectively. Validation of the acenocoumarol dose algorithms in the Rotterdam study cohort, has showed equal performance of the algorithms (Chapter 4). Subsequently, these algorithms are tested in a randomized controlled trial: the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial, of which the study design is presented in Chapter 5. Effects of genetic variance and comedication use on the anticoagulant therapy are described in Part III, chapter 6-9. We evaluate a possible gene-gene interaction between CYP2C9 and VKORC1 on the coumarin therapy and the effect of genetic variations in GATA-4 (the gene encoding for a CYP2C9 transcription factor), CYP3A4*1B, CYP3A4*22, CYP4F2 V433M and statin use on the phenprocoumon and acenocoumarol maintenance dose. The most promising findings are the decreased acenocoumarol, but not phenprocoumon, dose requirements for patients who use concurrently atorvastatin, simvastatin, pravastatin or rosuvastatin. In Chapter 10 we elaborate on the studies that are described in this thesis. The main findings are discussed and placed in a broader perspective. It is argued how to implement pharmacogenetics in a clinical setting and which parties are involved. The facilities required for implementation are considered and the cost-effectiveness and technical developments in pharmacogenetics are discussed. Finally, recent developments regarding the new oral anticoagulants (NOACs) are discussed and suggestions for future research are provided
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